CN112516331B - Method for improving water solubility and bioavailability of hesperidin - Google Patents
Method for improving water solubility and bioavailability of hesperidin Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical preparations, and discloses a method for improving the water solubility and bioavailability of hesperidin, which adopts a cyclodextrin embedding method, utilizes an alkaline system for solubilization, embeds the hesperidin in an inner cavity of cyclodextrin to prepare an hesperidin-cyclodextrin embedding substance, obviously improves the water solubility of the hesperidin, simultaneously avoids the side reaction of hesperidin ring opening caused by the conventional technical means, ensures the structural integrity of the hesperidin, and obviously improves the oral bioavailability of the hesperidin.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a method for improving the water solubility and bioavailability of hesperidin.
Background
Hesperidin (Hesperidin) is also called Hesperidin and Hesperidin, and is a glycoside formed by hesperetin and rutinoside, and is a dihydroflavone derivative. Is widely used in citrus plants of Leguminosae, labiatae, platycladaceae, rutaceae, and has effects of maintaining normal osmotic pressure of blood vessel, reducing vascular fragility, enhancing capillary toughness, and shortening bleeding time. The hesperidin has effects of reducing cholesterol in human body, resisting virus, and enhancing immunity, and has pharmacological activities such as antiinflammatory, antioxidant, antibacterial, anticancer, radioprotective, and cardiovascular system protecting effects.
Hesperidin has poor water solubility, which greatly limits its clinical application. The structural formula of hesperidin is shown in figure 1. In order to improve the solubility of the hesperidin in water, a learner can improve the solubility of the hesperidin in water by more than 10000 times through glycosylation modification, so that the solubility of the hesperidin in water is greatly improved, and the application range and the use effect of the hesperidin are improved. However, since the structure of hesperidin is changed after glycosylation, the in vivo absorption and metabolism behaviors are changed, and pharmacodynamics is still to be examined.
Based on the characteristic of indissolvable water of the hesperidin oil, the technical means of the invention improves the solubility of the hesperidin in aqueous solution by preparing the cyclodextrin inclusion compound of the hesperidin, and provides important support for good oral absorption of the hesperidin. However, because hesperidin is hardly soluble in water and is insoluble in conventional organic solvents, it presents difficulties for cyclodextrin entrapment. The research result shows that the hesperidin has the best dissolving effect in three solvents of dimethyl sulfoxide (DMSO), pyridine, N, N-Dimethylformamide (DNF), but the preparation of the hesperidin cyclodextrin inclusion compound can be realized by adopting the three solvents, but the serious defect that the solvents cannot be removed exists, and the preparation process of medicine development is not suitable for the preparation process of the medicine because the DMSO, the DMF and the pyridine have larger toxicity.
In addition, it has been shown that hesperidin is easily dissolved in an alkaline solution and the preparation of hesperidin cyclodextrin inclusion compound is carried out using a sodium hydroxide solution, however, the dissolution of hesperidin in an alkaline environment is due to the formation of by-products of ring opening thereof, and the structure is destroyed. According to the technical literature report of the prior art, cyclodextrin is adopted to clathrate the hesperidin, meanwhile, the structure of the hesperidin is not destroyed, and no similar technical report exists.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings in the prior art, and provides a method for improving the water solubility and bioavailability of hesperidin, wherein a specific alkaline system is adopted to realize the preparation of an hesperidin cyclodextrin embedding substance, so that the technical effect of obviously improving the water solubility of hesperidin is realized, meanwhile, the side reaction of hesperidin ring opening caused by the conventional technical means is avoided, the structural integrity of hesperidin is ensured, and the oral bioavailability of hesperidin is obviously improved.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for improving water solubility and bioavailability of hesperidin comprises adopting cyclodextrin embedding method, solubilizing with alkaline system, embedding hesperidin in inner cavity of cyclodextrin, and preparing hesperidin-cyclodextrin embedding substance.
Preferably, the alkaline system is obtained by organic base modulation.
Preferably, the organic base comprises one or more of diethylamine, ethylenediamine and triethylamine.
The molecular structure of hesperidin must not be destroyed in the cyclodextrin embedding process, and ring-opening reaction, hydrolysis reaction or ester-forming and salt-forming reaction must not occur. The study shows that the hesperidin is easy to have side reactions such as ring opening and the like under alkaline conditions, but the system of adjusting the pH by using organic alkali can lead the hesperidin to be more stable and the structure to be not damaged.
Preferably, the hesperidin content in the hesperidin-cyclodextrin inclusion is higher than 98%.
The solubility of the hesperidin in the cyclodextrin can be greatly increased by utilizing an alkaline system regulated by organic alkali for solubilization, the solubility is not destroyed, and the embedded matter with extremely high content and extremely few impurities can be obtained. The content of the prepared hesperidin-cyclodextrin inclusion is up to more than 98% by high performance liquid chromatography area normalization method.
Preferably, the method comprises the following steps:
(1) Preparing an aqueous solution of cyclodextrin, dissolving the cyclodextrin in water, heating and stirring to fully dissolve the cyclodextrin, and enabling the solution to be saturated to obtain the aqueous solution of cyclodextrin;
(2) Adjusting the pH value of the cyclodextrin aqueous solution to 11-12;
(3) Adding hesperidin into the cyclodextrin aqueous solution with the pH value adjusted, and heating and stirring at 40-60 ℃ to completely dissolve the hesperidin;
(4) Maintaining the temperature unchanged, continuing stirring for 2-10 h, and fully embedding;
(5) Drying to obtain the hesperidin-cyclodextrin embedding substance.
In the specific preparation process, the alkaline system is regulated, and then the hesperidin is added, so that the damage to the hesperidin caused by the local too high pH value is avoided.
Preferably, in the step (2), the pH of the cyclodextrin aqueous solution is adjusted to 11.5 to 12.
The stronger the alkalinity, the better the solubilization, but at the same time the greater the likelihood of the hesperidin structure being destroyed. Experiments show that the pH is in the range of 11-12, especially 11.5-12, and the hesperidin structure can be effectively solubilized while the hesperidin structure is not destroyed.
Preferably, the mass ratio of the hesperidin to the cyclodextrin is 1:1 to 9.
Preferably, the mass ratio of the hesperidin to the cyclodextrin is 1:2 to 4.
Preferably, the cyclodextrin comprises one or more of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, modified derivatized cyclodextrin, cyclodextrin ether derivatives, cyclodextrin ester derivatives, bridged cyclodextrin, cyclodextrin cross-linked polymer, cyclodextrin linked to a macromolecule, and cyclodextrin modified by an intercalating functional group.
Preferably, the cyclodextrin comprises one or more of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, HP-beta-cyclodextrin.
As an embedding system, cyclodextrin substances with embedding cavities, such as alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, HP-beta-cyclodextrin, modified derivatized cyclodextrin, cyclodextrin ether derivatives, cyclodextrin ester derivatives, bridged cyclodextrin, cyclodextrin crosslinked polymer, cyclodextrin connected with a high polymer, cyclodextrin modified by an embedded functional group and the like can achieve similar effects, and preferably, cyclodextrin which is easy to obtain, such as alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, HP-beta-cyclodextrin and the like can obtain better embedding effect with the help of an alkaline system. Wherein, HP-beta-cyclodextrin is introduced with hydroxypropyl based on beta-cyclodextrin, the introduction of hydroxypropyl breaks through the intramolecular cyclic hydrogen bond of beta-cyclodextrin, and the main defect of poor water solubility of beta-cyclodextrin is overcome while the cyclodextrin cavity is maintained. Better solubility means that more hesperidin is entrapped in a smaller volume of solvent, and the inclusion of HP-beta-cyclodextrin is a preferred option.
Preferably, in the step (5), the drying includes one or more of reduced pressure drying, vacuum drying, spray drying, and freeze drying.
Removing water contained in the cyclodextrin solution by common drying means such as vacuum drying, spray drying, and freeze drying to obtain hesperidin-cyclodextrin embedding substance. Wherein, the hesperidin-cyclodextrin inclusion prepared by spray drying and freeze drying has smaller particle size and higher solubility, and is regarded as a preferred option.
Compared with the prior art, the implementation of the invention has the following beneficial effects:
(1) the cyclodextrin is adopted for embedding, so that the water solubility of the hesperidin is greatly improved compared with the hesperidin raw material;
(2) after cyclodextrin is adopted for embedding, compared with the hesperidin raw material, the oral bioavailability of the material is greatly improved;
(3) according to the technical scheme, a specific alkaline system is adopted to prepare the hesperidin cyclodextrin inclusion, so that the use of toxic reagents is avoided, and the problem that a solvent cannot be removed is solved;
(4) according to the technical scheme, the problem that the structure of the hesperidin is damaged in an alkaline environment is solved, and the structure of the hesperidin is not changed on the premise of improving the solubility and bioavailability.
Disclosure of Invention
FIG. 1 is a structural formula of hesperidin;
FIG. 2 is a graph of the dissolution profiles of the different media of the hesperidin-HP-beta-cyclodextrin group;
FIG. 3 is a graph of the dissolution profiles of different media for a hesperidin feed group;
FIG. 4 is a view of an examination of hesperidin cyclodextrin inclusion prepared by different alkaline systems;
FIG. 5 is a view showing the examination of hesperidin cyclodextrin inclusion compounds of different pH systems
FIG. 6 is a graph of hesperidin, hesperidin beta-CD, hesperidin phospholipid complex drug time.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings, for the purpose of making the objects, technical solutions and advantages of the present invention more apparent.
Example 1
10g of beta-cyclodextrin is weighed, 100mL of purified water is added, the cyclodextrin is heated and stirred at 50 ℃ to fully dissolve, the pH is regulated to 11.5 by triethylamine, 5g of hesperidin raw material medicine (shown in figure 1) is added, and stirring is continued at 50 ℃ to fully dissolve hesperidin. And continuing stirring for 3 hours at 50 ℃ to fully embed, after embedding, firstly performing reduced pressure drying to remove part of triethylamine, and then performing spray drying to obtain the hesperidin-beta-cyclodextrin sample. 14.74g of product are finally obtained with a yield of 98.27%. The hesperidin before and after embedding was subjected to solubility measurement, and its solubility in water, pH1.2, pH4.5, and pH6.8 was measured. The water distribution coefficient was measured. The results showed that after inclusion by cyclodextrin, the solubility of hesperidin in water was increased from 0.0165mg/mL to 5.9533mg/mL before inclusion.
TABLE 1 example 1 measurement of solubility and oil-water partition coefficient before and after embedding hesperidin
Example 2
25g of HP-beta-cyclodextrin is weighed, 200mL of purified water is added, the cyclodextrin is heated and stirred at 60 ℃ to fully dissolve, the pH is regulated to 11.8 by diethylamine, 10g of hesperidin raw material medicine (shown in figure 1) is added, and stirring is continued at 60 ℃ to fully dissolve hesperidin. And continuing stirring at 60 ℃ for 2 hours to fully embed, and after embedding, performing spray drying to obtain the hesperidin-beta-cyclodextrin sample. 34.12g of product was finally obtained in 97.49% yield. The hesperidin before and after embedding was subjected to solubility measurement, and its solubility in water, pH1.2, pH4.5, and pH6.8 was measured (37 ℃ C., shaking for 24 hours). The water distribution coefficient was measured. The results showed that after inclusion by HP-beta-cyclodextrin, the solubility of hesperidin in water was increased from 0.0165mg/mL to 6.3327mg/mL before inclusion.
TABLE 2 measurement of solubility and oil-Water partition coefficient of hesperidin before and after embedding example 2
Example 3
30g of alpha-cyclodextrin is weighed, 500mL of purified water is added, the cyclodextrin is heated and stirred at 40 ℃ to fully dissolve, the pH is regulated to 11.96 by ethylenediamine, 6g of hesperidin raw material medicine (shown in figure 1) is added, and stirring is continued at 40 ℃ to fully dissolve hesperidin. And continuing stirring at 40 ℃ for 6 hours to carry out full embedding, after embedding, firstly drying out part of ethylenediamine by decompression, and then obtaining loose hesperidin-alpha-cyclodextrin inclusion compound by freeze drying. 44.27g of the product was finally obtained in a yield of 98.38%. The hesperidin before and after embedding was subjected to solubility measurement, and its solubility in water, pH1.2, pH4.5, and pH6.8 was measured (37 ℃ C., shaking for 24 hours). The water distribution coefficient was measured. The results showed that after inclusion by alpha-cyclodextrin, the solubility of hesperidin in water was increased from 0.0165mg/mL to 4.6542mg/mL before inclusion.
TABLE 3 measurement of solubility and oil-Water partition coefficient of hesperidin before and after embedding
Example 4
15g of gamma-cyclodextrin is weighed, 200mL of purified water is added, the cyclodextrin is heated and stirred at 45 ℃ to fully dissolve, the pH is regulated to 11.70 by ammonia water, 15g of hesperidin raw material medicine (shown in figure 1) is added, and stirring is continued at 45 ℃ to dissolve hesperidin. And continuing stirring for 5 hours at 45 ℃ to fully embed, after embedding, drying part of ammonia water by decompression, and then obtaining the hesperidin-gamma-cyclodextrin inclusion compound by spray drying. 28.96g of the product was finally obtained in a yield of 96.53%. The hesperidin before and after embedding was subjected to solubility measurement, and its solubility in water, pH1.2, pH4.5, and pH6.8 was measured (37 ℃ C., shaking for 24 hours). The water distribution coefficient was measured. The results showed that after inclusion by gamma-cyclodextrin, the solubility of hesperidin in water was increased from 0.0165mg/mL to 4.8862mg/mL before inclusion.
TABLE 4 measurement results of solubility and oil-water partition coefficient before and after embedding of hesperidin in example 4
Effect example 1
The solubility of the hesperidin can be greatly improved after the cyclodextrin inclusion is adopted, but the known technical scheme can not be used for preparing a successful hesperidin-cyclodextrin inclusion compound due to the characteristic that the hesperidin is extremely insoluble. If solvent such as DMSO and DMF is adopted to dissolve hesperidin so as to prepare the hesperidin-cyclodextrin inclusion compound, the solvent faces the problem of irremovable removal, so that the technical scheme creatively uses the characteristic of volatilizing and removing nitrogenous base such as ethylenediamine, diethylamine, triethylamine and the like, and is firstly used for dissolving the hesperidin, then cyclodextrin inclusion is carried out, and then the hesperidin-cyclodextrin inclusion product is finally obtained after inclusion is removed by a specific technical means, thus the solubility of the hesperidin is greatly improved, and in-vitro dissolution is compared by adopting the hesperidin raw material and the hesperidin-beta-cyclodextrin respectively for fully evaluating the technical scheme effect of the invention.
The dissolution rates of the hesperidin tablet and the hesperidin-beta-cyclodextrin tablet in four media of water, pH1.2, pH4.5 and pH6.8 are examined by adopting a method of directly tabletting the powder. The tablet formulation is shown in table 5, wherein hesperidin-beta-cyclodextrin was prepared according to example 2. Sampling time points are 5, 10, 15, 20, 30, 45 and 60min respectively. The sampling volumes were 5mL, absorbance measurements at each time point were performed using an ultraviolet spectrophotometer, and content measurements were performed by an external standard method. The final time-percent release profile was plotted, with the results for the hesperidin-beta-cyclodextrin tablet set shown in fig. 2 and the results for the hesperidin tablet set shown in fig. 3.
Table 5 preparation of hesperidin and hesperidin-beta-cyclodextrin tablet formulation
As can be seen from fig. 2 and 3, the solubility of the hesperidin raw material group in each medium is extremely low, the release of the hesperidin raw material group in 60min is still low, and the solubility of the hesperidin raw material group is greatly improved after the hesperidin raw material group is prepared into the cyclodextrin inclusion compound, so that the hesperidin raw material group can be released to be more than 85% completely in 15-20 min. The release platform of the hesperidin raw material group is maintained between 3 and 4 percent, so that the in-vitro release degree of the hesperidin-cyclodextrin inclusion compound can be greatly improved after the hesperidin-cyclodextrin inclusion compound is prepared, and the feasibility of preparation development is greatly improved.
Effect example 2
In order to fully evaluate the beneficial effects of the technical scheme, the influence test of various alkaline systems on the hesperidin structure is carried out, and the preparation of the hesperidin cyclodextrin inclusion is carried out by adopting systems such as sodium hydroxide, potassium hydroxide, ammonia water, triethylamine, diethylamine and the like, and the analysis and the detection are carried out by adopting a high performance liquid chromatography method, so that the influence of different alkaline systems on the hesperidin can be evaluated. The analytical test results are shown in FIG. 4.
As can be seen from FIG. 4, when the conventional alkaline system such as sodium hydroxide and potassium hydroxide is adopted, the prepared hesperidin cyclodextrin inclusion compound has obvious impurity peak generation at 6.5min, is mainly a ring-opening product of hesperidin, and has obvious impurity generation at 4min by adopting ammonia water as the alkaline system, and the degradation rate of hesperidin is as high as more than 50%. And diethylamine and triethylamine are used as alkaline systems, the purity of the prepared hesperidin cyclodextrin inclusion reaches more than 98%, and no obvious impurity is generated. Therefore, the hesperidin cyclodextrin inclusion prepared by adopting diethylamine and triethylamine as alkaline systems does not damage the structure of hesperidin
Effect example 3
In order to investigate the influence of different pH values on the hesperidin-cyclodextrin inclusion compound, the formulation and the preparation process as in example 1 were adopted, wherein the difference is that the pH values of the cyclodextrin aqueous solutions were respectively adjusted to 8, 9, 10, 11, 12, 13 and 14, and after the hesperidin-cyclodextrin inclusion compound was prepared, the drug loading and the hesperidin content were respectively detected and recorded, and the results are shown in FIG. 5.
As can be seen from fig. 5, when the pH is less than 11, the drug loading rate of the prepared cyclodextrin inclusion compound is too low, because the amount of the hesperidin which is embedded into the cyclodextrin cavity is reduced due to the fact that the hesperidin cannot be completely dissolved when the pH is less than 11, so that the drug loading rate is low; and when the pH is more than 12, the purity of the prepared hesperidin cyclodextrin inclusion compound is obviously reduced, which is caused by the increase of byproducts caused by the over-high alkalinity. The method shows that when diethylamine, ethylenediamine or triethylamine is used as an alkaline system to prepare the hesperidin cyclodextrin inclusion, the pH value of the system needs to be strictly controlled between 11 and 12.
Effect example 4
To further evaluate the inventive effect of the technical scheme of this patent, the oral bioavailability of hesperidin, hesperidin-beta-cyclodextrin was studied and compared with the hesperidin phospholipid complex of literature (preparation, characterization and in vivo pharmacokinetic studies of hesperidin phospholipid complex solid dispersion, niu Xiaolei, gu Runxia, xiu feng, chinese patent medicine, 9 of 2020, volume 42, 9 th phase).
And respectively taking the hesperidin bulk drugs, adding a proper amount of hesperidin-beta-CD into a 0.5% CMC-Na solution, and carrying out ultrasonic treatment for 10s to obtain the medicine (the dosage is 8mg/mL in terms of hesperidin). SPF-grade SD rats were divided into hesperidin drug substance group and hesperidin-beta-CD group at random after overnight fast, and 6 rats each were administered at 80 mg/kg. Blood was collected from the orbits at 0.167, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10 and 12 hours after administration, and 0.2mL each was placed in a heparin-containing centrifuge tube, centrifuged at 3000rpm/min for 10min, and the supernatant was analyzed by HPLC, and the blood concentration and sampling time measured by HPLC were recorded, and compared with the data of the hesperidin phospholipid complex recorded in the literature, and the results are shown in Table 6. A graph was drawn to obtain a time-of-drug curve, and the results are shown in fig. 6.
TABLE 6 comparison of pharmacokinetic parameters of hesperidin, hesperidin-beta-CD, hesperidin-phospholipid complexes
| Parameters (parameters) | Unit (B) | Hesperidin raw material group | hesperidin-beta-CD | Hesperidin phospholipid complex |
| T max | h | 1.0000 | 1.0000 | 0.97±0.14 |
| t 1/2 | h | 2.0212±0.1321 | 2.405±0.1479 | 3.77±0.62 |
| C max | ug*mL -1 | 1.987±0.1515 | 7.6536±0.7832 | 4.13±0.89 |
| AUC 0～t | ug*mL*h | 4.2387±0.3803 | 21.8310±2.4448 | 10.53±2.11 |
| AUC 0～8 | ug*mL*h | 4.3285±0.4282 | 22.3825±2.5065 | 11.06±2.29 |
According to the drug time curve shown in Table 6 and the key pharmacokinetic parameters combined with FIG. 6, it is evident that, at the same administration dose, hesperidin-beta-CD has higher bioavailability than hesperidin and its phospholipid complex, which is mainly beneficial to greatly increasing the solubility of hesperidin due to cyclodextrin embedding, thereby significantly improving the oral absorption availability thereof.
The foregoing disclosure is merely illustrative of the preferred embodiments of the present invention and is not intended to limit the scope of the claims herein, as equivalent changes may be made in the claims herein without departing from the scope of the invention.
Claims (6)
1. A method for improving the water solubility and bioavailability of hesperidin is characterized in that a cyclodextrin embedding method is adopted, an alkaline system is utilized for solubilization, and hesperidin is embedded in an inner cavity of cyclodextrin to prepare an hesperidin-cyclodextrin embedded substance;
the preparation method comprises the following steps:
(1) Preparing an aqueous solution of cyclodextrin, dissolving the cyclodextrin in water, heating and stirring to fully dissolve the cyclodextrin to obtain the aqueous solution of cyclodextrin;
(2) Adjusting the pH value of the cyclodextrin aqueous solution to 11-12;
(3) Adding hesperidin into the cyclodextrin aqueous solution with the pH value adjusted, and heating and stirring at 40-60 ℃ to completely dissolve the hesperidin;
(4) Maintaining the temperature unchanged, continuously stirring for 2-10 hours, and fully embedding;
(5) Drying to obtain an embedding substance of hesperidin-cyclodextrin;
the alkaline system is obtained by regulating organic alkali; the organic base is one or more of diethylamine, ethylenediamine and triethylamine; the mass ratio of the hesperidin to the cyclodextrin is 1: 1-9.
2. The method of claim 1, wherein the hesperidin content of the hesperidin-cyclodextrin inclusion is higher than 98%.
3. The method for improving the water solubility and bioavailability of hesperidin according to claim 1, wherein in the step (2), an organic base is used to adjust the pH of the cyclodextrin aqueous solution to 11.5-12.
4. A method of improving the water solubility and bioavailability of hesperidin according to claim 3, characterized in that the mass ratio of hesperidin to cyclodextrin is 1: 2-4.
5. A method of improving the water solubility and bioavailability of hesperidin according to claim 3, wherein the cyclodextrin is one or more of α -cyclodextrin, β -cyclodextrin, γ -cyclodextrin, HP- β -cyclodextrin.
6. The method of claim 3, wherein in step (5), the drying comprises one or more of drying under reduced pressure, vacuum drying, spray drying, and freeze drying.
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